SUMMARY Columnar metaplasia, including Barrett?s esophagus (BE), is considered a precursor lesion of esophageal adenocarcinoma which has seen a 600% fold increase in incidence over the last three decades. BE occurs exclusively at the esophageal-gastro junction where the stratified squamous epithelium transitions into simple columnar cells. In patients with BE the junction moves anteriorly and the columnar epithelium is expanded, meanwhile gaining intestinal differentiation characteristics in some cases. Significantly, the cell-of-origin of the metaplastic columnar epithelium remains controversial. Here, we identify a novel pseudostratified epithelium maintained by a unique basal progenitor cell population (p63+, KRT5+, KRT7+) at the squamous-columnar junction (SCJ). Our preliminary data suggest that the unique epithelium serves as the origin for BE metaplastic epithelium in multiple mouse models. Our data further indicate that Wnt signaling promotes metaplastic changes at the SCJ. We therefore hypothesize that columnar metaplasia including BE is derived from the unique basal progenitor cells (p63+, KRT5+, KRT7+), a process promoted by Wnt signaling. We will test the hypothesis with three specific aims: Aim 1: To further test that the basal progenitor cells (p63+, KRT5+, KRT7+) are the cells- of-origin for columnar metaplasia including BE. Aim 2: To test the hypothesis that Wnt signaling promotes columnar metaplasia at the SCJ and that inhibition of this signaling blocks disease progression. Aim 3: To model the human BE pathogenic process with hESC-derived basal progenitor cells of the columnar epithelium. We have established a robust in vitro system to induce the differentiation of human embryonic stem cells towards basal cell fate. In this aim we will use this system to understand the mechanism driving the abnormal differentiation of basal cells during BE development. Together findings from this project will contribute important insights into early BE pathogenesis and provide potential therapeutic targets for treatment.